Viruses are among the most frequent causes of acute and chronic illness, and newly discovered viruses continue to cause emergent diseases that resist established vaccines. Despite the scope of this problem, the accuracy of diagnosis and efficacy of treatment for most viral infections, especially new types of infections, is very limited in effectiveness. To address this issue, we have developed an alternative strategy that is aimed at defining and then improving the antiviral host response. We focus particularly on respiratory infection since this is a common route of natural infection and a likely route for delivery of bioterrorist threats. In that regard, we have developed a system for primary-culture and infection of human airway epithelial cells that exhibits high fidelity to behavior found in vivo. Our analysis of this epithelial cell model in concert with a corresponding mouse model indicates that antiviral defense against respiratory viral infection depends critically on interferon (IFN) activation of the Stall signaling molecule in airway epithelial cells. Based on these findings, we proposed that improving Stall function in airway epithelial cells would enhance antiviral defense. Accordingly, we engineered a modified Stall with strategic double-cysteine mutalions (designaled Slal1-CC) that is hyperresponsive to endogenous interferon levels. Expression of Stall-CC should thereby enhance interferon-signaling function and provide for better control of viral replication. Indeed, our Preliminary Studies demonstrate that Stall-CC expression markedly decreases Ihe level of viral replication both in vitro (using transduced cells) and in vivo (using transgenic or gene transfer technology). For example, mice carrying the Stall-CC transgene or treated with a Stall-CC gene-transfer vector are fully protected against otherwise lethal infections due to each of the three viruses studied thus far. Furthermore, we have observed no toxicities of Stall-CC expression, in contrast to the situation for direct administralion or overexpression of interferon itself. In this proposal, we aim to extend our approach to the study of emergent pathogens with the capability for epidemic spread through the human population. In doing so, we aim to establish infection capabilities and diagnostic signatures for these new viruses, a new therapeutic strategy for these pathogens, and a better understanding of innate immunity to these agents.